White adipose tissue (WAT) is composed of several cell types. The TG-storing cell is called the adipocyte. These cells develop from preadipocytes during gestation in humans. This process of adipocyte differentiation, which may continue throughout life, is promoted by several transcription factors. One of these factors is SREBP1C, which is activated by lipids as well as insulin and several growth factors and cytokines. Another important transcription factor in WAT is PPARγ. Activated PPARγ promotes expression of genes involved in TG storage. Thus an increase in food consumption leads to activation of SREBP1C and PPARγ, which increase the differentiation of preadipocytes into small adipocytes and upregulation of enzymes within these cells to allow storage of excess fat.
Adipose tissue produces paracrine and endocrine factors, including adiponectin, TNF-α, resistin, interleukin-6, angiotensinogen, and acylation-stimulating protein.
Leptin is an adipocyte-derived protein that signals information to the hypothalamus about the degree of adiposity and nutrition, which in turn controls eating behavior and energy expenditure. Leptin-deficient mice and humans become morbidly obese. These findings originally raised hope that leptin therapy could be used to combat morbid obesity. However, administration of leptin to individuals who suffer from diet-induced obesity does not have a significant anorectic or energy-consuming effect. In fact, obese individuals already have elevated endogenous circulating levels of leptin and appear to have developed leptin resistance.
Leptin has an important role in liporegulation in peripheral tissues. Leptin protects peripheral tissues (e.g., liver, skeletal muscle, cardiac muscle, beta cells) from accumulation of too much lipid by directing storage of excess caloric intake into adipose tissue. This action of leptin, though opposing the lipogenic actions of insulin, contributes significantly to maintenance of insulin sensitivity (as defined by insulin-dependent glucose uptake) in peripheral tissues. Leptin also acts as a signal that the body has sufficient energy stores to allow reproduction and to enhance erythropoiesis, lymphopoiesis, and myelopoiesis. For example, in women suffering from anorexia nervosa, leptin levels are extremely low and result in low ovarian steroids, amenorrhea (lack of menstrual bleeding), anemia from low red blood cell production, and immune dysfunction.
Structure, Synthesis, and Secretion
Leptin, a 16-kDa protein secreted by mature adipocytes, is structurally related to cytokines. Thus it is sometimes
SREBP2 wasdiscoveredasatranscriptionfactorthatresidesinthemembraneoftheendoplasmicreticulum(ER).Inthepresenceofhighintracellularcholesterol,SREBP2isheldintheERbyalipid-sensingproteincalledSCAP (SREBPcleavage–activatingprotein).Inresponsetodepletedsterols,SCAPescortsSREBP2totheGolgi,whereSREBPiscleavedsequentiallybyproteasesandreleasedintothecytoplasm.SREBP2thentranslocatestothenucleusandincreasesthetranscriptionofgenesinvolvedinsynthesisanduptakeofcholesterol.AmorerecentlydiscoveredmemberofthistranscriptionfactorfamilyisSREBP1C, whichishighlyexpressedinadiposeandliver.IncontrasttoSREBP2,SREBP1CstimulatesgenesinvolvedinsynthesisofFAandTG.RegulationofSREBP1CoccursatthetranscriptionalleveloftheSREBP1C gene,withcleavageinducedbypolyunsaturatedfattyacidsandactivationbytheMAPKpathway.